The long-term objective is to understand the mechanisms and conditions necessary for the destruction of well-established solid tumors by adoptive transfer of tumor-specific CD8+ T cells (CTL). Success with this therapy depends on the elimination of cancer cell variants which requires (i) adequate numbers of activated T cells secreting optimal amounts of appropriate effector molecules, and (ii) cross-presentation of tumor- specific antigens by tumor stroma whose destruction is necessary to prevent the outgrowth of resistant cancer cell variants. Escape of cancer variants is the most common reason for the failure of various types of cancer therapy. The first three Aims determine the requirements for complete cancer rejection by CTL when cancer cells contain sufficient tumor-specific antigen. The fourth Aim develops novel approaches to overcome the problem in tumors with low tumor antigen levels that seem to predispose to escape of variants. The last Aim explores tumor-specific mutant-self antigens and tumor-associated self antigens over- expressed by cancer cells as targets for stromal destruction by CD8+ T cells from tumor-bearing hosts. Thus, the Specific Aims are to: 1. Determine which stromal cells or stromal cell types must express which cytdkihe receptors for allowing complete tumor rejection. 2. Determine whether destruction of cancer cell variants is caused by necrosis or apoptosis. 3. Determine whether endothelial cells and Tie2-expressing CD11b+ BM-derived cells are the relevant targets for CD8+ T cells in tumor stroma. 4. Develop ways to load more antigen into the stroma when levels of antigen expressed by cancer cells .are low. 5. Compare and determine whether CTL reactive to over-expressed self antigen, reactive to mutant-self antigen, or CTL derived from tumor-bearing animals cause bystander killing of stroma and antigen-loss variants. The mechanisms will be studied in murine tumor models using transfected tumor-specific model antigens, mice genetically deficient in defined effector or receptor molecules, and T cells from TCR-transgenic mice. Confirmation of the critical findings will also be sought by using non-TCR transgenic T cells and by targeting self or mutant-self tumor antigens. The Aims capitalize on the use of recently developed probes and reagents available that will should allow high resolution results and lead to novel approaches to maximize destruction of tumor stroma and cancer cell variants. Together, understanding the phenomenon of stromal destruction, stromal cell loading, and bystander elimination of cancer variants should help to define the requirements for successful CD8+ T cell-mediated immunotherapy of solid tumors. The findings to be made are expected to guide the design of realistic new approaches for cancer therapy that overcomes cancer escape.